Metabolic syndrome is a condition that is characterized by having two of at least five metabolic disorders that include abdominal obesity, low levels of high-density lipoprotein (HDL) cholesterol, high blood pressure, and high fasting blood sugar.

“We’ve studied xanthohumol for many years. We think what we have now is a big improvement,” said author Fred Stevens, who is a professor of pharmaceutical sciences at the College of Pharmacy at Oregon State University and a principal investigator at Oregon State’s Linus Pauling Institute.

While past research had pointed to evidence that XN could be a possible treatment for metabolic syndrome, what makes XN so problematic is the fact that it transforms itself into 8-prenylnaringenin, or 8-PN, an estrogenic metabolite. Taking XN for a long period of time can lead to estrogenic side effects, which include endometriosis and breast cancer.

“We were always criticized about the potential side effects because 8-PN is one of the most phytoestrogens known in nature, and that’s not good news. If someone took XN over longer periods of time, it could lead to estrogenic side effects, potentially,” Stevens said.

“A double bond in the XN molecule is responsible for that 8-PN metabolism to be possible, so I thought if I could get rid of that double bond by hydrogenating the molecule, then that metabolite cannot be formed anymore. I thought maybe this was the solution to the problem.”

In the experiment that the researchers did with mouse models, it was found out that XN and its hydrogenated derivatives, DXN and TXN, boost glucose tolerance and insulin resistance, and sensitivity to leptin, which is a hormone that tells the body that it is already full after a meal and which also aids in energy expenditure.

It was also found out that the derivatives were even more effective than XN itself, as they don’t result in estrogenic metabolite and they don’t have the propensity to establish estrogen receptors.

“TXN is especially potent in reducing insulin resistance in mice made obese by feeding a high-fat diet. Probably the bioavailability of the hydrogenated derivatives is better than for XN itself – that would explain why they work better. Now we have compounds that still have the original beneficial effects but not the side effects,” said researcher Cristobal Miranda, an associate professor at the Linus Pauling Institute.

“There are no adverse estrogenic effects, and the liver toxicity induced by the high-fat diet is mitigated. Our mouse study showed that XN, DXN, and TXN are not hepatotoxic,” Stevens said.

When the researchers tested mice in a water maze, it was found out that XN and its derivatives fixed impairments in spatial learning and memory induced by the high-fat diet that the mice had been given.

“These findings could be important for people suffering from cognitive impairments associated with a high-fat diet and metabolic syndrome. Our findings with rodents suggest that it may be possible to reduce or even prevent learning and memory impairments through a derivative of the same chemical compound found in beer,” said study co-author Jacob Raber, who is an affiliate scientist in the division of neuroscience at the Oregon National Primate Research Center.